The overall goal of this proposal is to understand the signal transduction mechanisms of the Ras protooncogene. It is well established that Ras acts as a molecular switch existing between GDP- and GTP- bound forms. The GTP-bound Ras is active, and directly binds to and regulates downstream effector molecules while GDP-bound Ras is thought to be inactive. Recent evidence suggests that GDP-bound Ras may also have signaling functions rather than being an inactive form as predicted by the current model. The investigator has found that smgGDS (small GTPase GDP dissociation stimulator), which is an activator for several small GTPases, specifically binds to GDP-bound but not GTP-bound H-Ras. The main goal of this proposal is now to demonstrate that GDP-bound Ras has an active role in signal transduction. The focus is to establish that GDP-bound Ras regulates the activities of smgGDS and to demonstrate that smgGDS functions as a physiological downstream effector for GDP-bound Ras. The specific aims are to examine: 1) Interaction between smgGDS and Ras-GDP; 2) Regulation of smgGDS activity by Ras; and 3) Role of smgGDS in Ras-GDP signal transduction